Chapter 9

N

OS Thiophenes

1

2

The simple thiophenes are stable liquids that closely resemble the corresponding benzene compounds in boiling points and even in smell. They occur in coal- tar distillates – the discovery of thiophene in coal-tar benzene provides one of the classic anecdotes of organic chemistry.

THIOPHENES

Reactions with electrophiles at C Preferably at C-2 / C-5 (α-positions)

3

X X E

H X E H X

E H

X

E H

X

E H

m o s t s t a b l e

E

E

X : N R , S , O

4

-Protonation • Much more stable under acidic conditions than pyrroles and furans • Protonation at C-2 /C-5

S

100% H3PO490 oC

SH

H SHH S

HH

5

The action of hot phosphoric acid on thiophene leads to a trimer; its structure suggests that, in contrast with pyrrole, the electrophile involved in the first C–C bonding step is the α-protonated cation.

C12H10S3

6

Nitration of thiophene needs to be conducted in the absence of nitrous acid, which can lead to an explosive reaction; the use of acetyl nitrate or nitronium tetrafluoroborate is satisfactory

Nitration

•Not complete selectivity •Not HNO3 (explosions)

S NO2" NO2+"

S NO2

O2N

+S NO2O2N

ca 1 : 1

S" NO2+"

S

NO2 NO2

O2NNO2: m-Directing

Reactions with electrophiles at C

7

Further nitration of either 2- or 3-nitrothiophenes also leads to mixtures: equal amounts of 2,4- and 2,5- dinitrothiophenes from the 2- isomer, and mainly 2,4- dinitrothiophene from 3-nitrothiophene.

8

9

Halogenation of thiophene occurs very readily at room temperature and is rapid even at − 30 °C in the dark; tetrasubstitution occurs easily. The rate of halogenation of thiophene at 25 °C is about 108 times that of benzene. 2-Bromo-, 2-chloro- and 2-iodothiophenes and 2,5- dibromo - and 2,5- dichlorothiophenes can be produced cleanly under various controlled conditions.

Halogenation

Bromination

S

2 Br2, 48% HBr

-25 — 5 oC SBr

2 Br2, 48% HBr

-10 — r.t S BrBr

3 Br2, 48% HBr

75 oC SBrBr

Br

NaBH4DMSO, r.t. SBr

Br

NaBH4, Pd(0)

MeCN, ∆ S Br

Br

ZnAcOH, ∆

S

Br

Reactions with electrophiles at C

Multibromination occurs readily at room temperature and even at -30 °C • Careful control or reaction conditions is required to ensure mono-bromination

10

One interpretation of the selective reductive removal is that it involves, first, electron transfer to the bromine, then transient ‘anions’, thus halogen can be selectively removed from that position where such an anion is best stabilised – normally an α-position

11

S

Br CuCl

DMF S

Cl

Iodination

S 90 oC

I2, HNO3(aq)

S I

S

Br CuI

DMF S

I

12

The Friedel – Crafts acylation of thiophenes is a much - used reaction and generally gives good yields under controlled conditions, despite the fact that aluminium chloride reacts with thiophene to generate tars; this problem can be avoided by using tin tetrachloride and adding the catalyst to a mixture of the thiophene and the acylating agent. Acylation with anhydrides, catalysed by phosphoric acid is an efficient method.

S S

RCOClSnCl4

FC acyl. O

R

POCl3, DMF(Vilsmeier)

SO

aldehyde

ketone

(strong Lewis acid, AlCl3 leads to polym.)

13

14

S

R

O

R'

H

S H

OHR'

R

+ res formsH-

SOH

R'R

H Decomp

15

Condensation with carbonyl compounds

Acid-catalysed reaction of thiophene with aldehydes and ketones is not a viable route to hydroxyalkyl - thiophenes, for these are unstable under the reaction conditions.

Condensation with carbonyl comps, cont.

S

CH2O, conc. HCl

0 oC SCl

16

17

18

Condensation with imines / iminium ions

Thiophene (and furan): Preformed reagent generally required

S MeCN, ∆ SN

Me2N=CH2 Cl

S SNH2

H2CO (aq)NH4Cl

But:

19

Another device for bringing thiophenes into reaction with Mannich intermediates is to utilise thiophene boronic acids – the Petasis reaction; primary aromatic amines can also be used as the amine component.

The Petasis reaction

Reactions with electrophiles at Sulfur

S

E

S

E

•Possible for thiophene; S in 3rd row •Not possible for furan / pyrrole; O and N in 2nd row •Probably sp3 S. tetrahedral •Works best for electron rich thiophenes

S S

Me

Me Me

Me Me

O SMe

O

OF

Me Me

Me Me

O SO

OF

NaPF6S

Me

Me Me

Me Me

PF6

+ FSO3Na

20

Reactions with electrophiles at Sulfur

React. with carbenes

S

RO2C CO2R

60 oC SCO2R

CO2R

H

SCO2R

CO2R

21

S

N N

R O 2 C C O 2 R

N N

R O 2 C C O 2 R

R h 2 ( O A c ) 4

-N 2 R O 2 C C O 2 R

C a r b e n e

S

R O 2 C C O 2 R 9 5 %

S t a b l e y l i d e

S

R O 2 C C O 2 R

Reactions with electrophiles at Sulfur

React. with carbenes

S

H

HH

O

OR

H

S

H O

OR

H

S

CO2R

22

N N

C O 2 R

1 ) R h 2 ( O A c ) 4 S

C O 2 R S

C O 2 R H

2 ) S

S

H

H

C O 2 R

H

? ? ? ? ? ?

Oxidation

S

[ox][ox]S

O OSO

Not aromatic

23

24

The oxidation of thiophene derivatives by hydrogen peroxide is catalyzed by methyltrioxorhenium(VII) (CH3ReO3). This compound reacts with hydrogen peroxide to form 1:1 and 1:2 rhenium peroxides, each of which transfers an oxygen atom to the sulfur atom of thiophene and its derivatives. Complete oxidation to the sulfone occurs readily by way of its sulfoxide intermediate.

Inorg. Chem., 1996, 35 (25), pp 7211–7216

Oxidation

25

SS

O O

R R mCPBAR R

R° Hrel. stable

EWG SR

R

OO

EWG- SO2- EWG-H

R

R

Oxidation

26

Reactions with nucleophiles

S NX

Nu

O

OS

NuX

NO

OS NO2Nu

Sulfurstab. neg, chargeon α-C

SNu

X NO

O

Nitro substituents activate the displacement of leaving groups like halide, as in benzene chemistry, and extensive use of this has been made in thiophene work. Such nucleophilic displacements proceed at least 102 times faster than for benzenoid counterparts, and this may be accounted for by participation of the sulfur in the delocalisation of charge in the Meisenheimer intermediate.

27

Reactions with nucleophiles

Reactions with nucleophiles

28

Nitrogroups also permit the operation of VNS processes, as illustrated below:

S N O

O S N

O

O

V i c a r i o u s N u s u b s t ( V N S )

E W G R

X H

R E W G X B a s e

S N

O

O

E W G R

H

S N O 2

E W G R

29

Copper and copper(I) salts have been used extensively in thiophene chemistry to catalyse displacement of bromine and iodine, but not chlorine, in simpler halo – thiophenes.

S

B r C u X

X = C l , I S

X

C u B r M e O N a

S

O M e

C-metallation and further reactions

In the 2 / 5 pos.

S

n-BuLi1 equiv. S Li

"E+"

S E

n-BuLi2 equivs.

S Li"E+"

S ELi E

3-Litiation with ODG

S CO2H

n-BuLi

LDAS CO2LiLi

S

Li

O

OLi

30

31

C-metallation and further reactions

32

Metal – Halogen Exchange

Bromine and iodine at either α - or β - positions undergo exchange with alkyllithiums giving lithiated thiophenes.

S

B r n - B u l i

- 7 0 o C S

L i " E + "

S

E

S t a b l e i n h e x a n e

33

Metal – Halogen Exchange

Rieke metals are highly reactive metal powders prepared by the methods developed by Reuben D. Rieke. Rieke metals are highly reactive because they have high surface area and lack surface oxides which retard reaction. Rieke metals are usually prepared by a reduction of a THF suspension of an anhydrous metal chloride with an alkali metal. Typical alkali metals used in this method are potassium, sodium, and lithium. For example, the preparation of Rieke magnesium employs potassium as the reductant:

MgCl2 + 2 K → Mg + 2 KCl

http://en.wikipedia.org/wiki/THF�

34

S

Li

In Et2O over -25 oC:

SLi

S

Met

Met: ZnX, MgXStable at RT

Reaction with radicals, Seldom synthetically usefull

35

Radicals generated in various ways have been utilised in elaborating thiophenes and in ring - closing reactions; examples are shown below:

36

Catalytic reductions of the thiophene ring, or of substituents attached to it, are complicated by two factors:

1- poisoning of the catalyst and 2- the possibility of competing hydrogenolysis – reductive removal of sulfur, particularly with Raney nickel

Indeed the use of thiophenes as templates on which to elaborate a structure, followed finally by desulfurisation, is an important synthetic strategy.

37

Cycloadditions

Unactivated thiophenes show little tendency to react as 4 π compon-ents in a Diels – Alder sense; however, maleic anhydride will react with thiophene to produce an adduct in high yield, under extreme conditions.

38

Electrophilic alkynes will react with thiophenes under vigorous conditions, though the initial adduct extrudes sulfur, and substituted benzenes are obtained as products. Thus, both α - and β - methoxy - substituted thiophenes react with dimethyl acetylenedicarboxylate in xylene to give modest yields of phthalates resulting from sulfur extrusion from initial adducts; in acetic acid as solvent, only substitution products are obtained.

Oxythiophenes

39

40

Aminothiophenes

c.f. Aminopyrroles -Amino (not iminoform) - unstable S NH2 S

NH2

Only aminoGenerally unstable

Synthesis of Thiophenes

S

a

b

c

d

S

S

S

S

41

42

Strategy a:

OO

HH LR

SS

HH

PS

MeOS

PS

SOMe

LR: Lawesons reagent

SSH

H

±H S

H

SH- H2S S

H

Carbonyl condensations

Strategy a, cont.:

43

Reactions with electrophiles at Sulfur

O O N a N a O

O S

P 4 S 1 0

When the process is applied to 1,4 - dicarboxylic acids, a reduction must occur at some stage, for thiophenes, and not 2- or 5-oxygenated thiophenes result.

44

SR R'H2S, NaOH R

R'HS

R R'

Much use has been made of conjugated diynes, which are also at the oxidation level of 1,4 – dicarbonyl compounds, which react smoothly with hydrosulfide or sulfide, under mild conditions, to give 3,4-unsubstituted thiophenes.

Use of conjugated diynes

45

3,4-ethylenedioxythiophene

46

Strategy b:

From α-Thio - Carbonyl Compounds

S P h 3 P

H S

O

S

O P h 3 P W i t t i g S

[ o x ] ( c h l o r o a n i l )

47 Chloranil:

http://en.wikipedia.org/wiki/File:2,3,5,6-tetrachloro-parabenzoquinone.svg�

48

Strategy c:

OO

R H

OHO

RHS

ORO

SHO

OR

O

OR H

- H2O S

OR

OH

OR

H

- H2O S

R

CO2R

From Thioglycolates and 1,3 - Dicarbonyl Compounds

49

Fiesselmann Thiophene Synthesis

The Fiesselmann thiophene synthesis involves the condensation reaction of thioglycolic acid derivatives with acetylenic esters, which upon treatment with base results in the formation of 3-hydroxy-2-thiophenecarboxylic acid derivatives.

51

52

Strategy d

S

d

S

53

54

RO2C S CO2RBase

RO2C S CO2R

R R

O O

RO2C S

OR

OR

S

O

O

OR RO2CR

ORO

H

Bsae

S

ROR

ORO2C

OBase

S

ROR

ORO2C

OSRO2C

R R

CO2

O

SRO2C

R R

CO2

OH

- OH

H

S

R R

CO2RRO2C

Mechanism:

55

Miscellaneous carbonyl reactions

S

R'

O R'O

1) Base

2) S=C=S R'

O R'O

SS

Base

R'

O R'O

SS

Br R

O R'

O R'O

SS O

R

Base

R'

O R'O

SS O

RSSO

R

OR' R'

OWater elim.S-alylation (R''X)

SSO

R

OR' R'

R''

56

Using Carbon Disulfide:

57

OR4

S

R3OTiCl4Zn

R2R5 S

HO OHR4 R3

R5H

R2H S

R4 R3

R5 R2- H2O

S

From Thio – Diketones:

Miscellaneous carbonyl reactions

Chapter 9Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Slide Number 49Fiesselmann Thiophene SynthesisSlide Number 51Slide Number 52Slide Number 53Slide Number 54Slide Number 55Slide Number 56Slide Number 57